Sickle cell disease (SCD) is the first genetic disease and a public health challenge in France. SCD was designated public health priority by UNESCO in 2003, the French Ministry of Health in 2004 and WHO in 2006. Although a rare disease, the affliction is a worsening challenge for health and social services. A sharp increase in patient numbers put sickle cell disease at the top position of genetic diseases in French metropolitan areas, concerning 5,000 to 6,000 patients up to 18 yo, with an estimated 20,000 patients by 2020. Carrier frequency reaches 12% in French West Indies and rises in the USA and developed countries. Demographic trends and the systematic diagnosis at birth for ethnics at risk are partly responsible for this sharp increase in cases to treat. SCD, the most common genetic disease of our time, will soon become a public health challenge in western countries and France in particular.
SCD results from a point mutation (HbS) in the hemoglobin gene, causing hemoglobin to polymerize, mediating drastic and irreversible remodeling of red blood cells (RBC). Here, sickle cell disease refers to the homozygous HbSS phenotype. Remodeled RBC aggregate and become trapped in microvessels, favoring painful vaso-occlusive crises (VOC). Ensuing hemolysis liberates ‘free’ hemoglobin and heme into the bloodstream, and RBC membrane fragments called microparticles (MP), which carry adhesion receptors and bind avidly to vascular and circulating cells. The mechanisms that rule over the occurence of VOC and hemolysis are not known in SCD.
There are virtually no specific drugs to treat or prevent VOC. Primary care for VOC is hospitalization to manage pain with powerful analgesics, combined with rehydration and oxygenation. No specific drug exists to prevent the occurrence or treat VOC. Long term hydroxy-urea treatment (since 1995) is sometimes prescribed to force the re-expression of fetal hemoglobin, to reduce sickle cell formation and ultimately reduce hemolysis. However, hydroxy-urea is only effective in about 40% of SCD patients, with presumptions of carcinogenesis in the long term. The most severe cases of VOC are eligible for blood transfusion, with the associated exposure to viral infection and secondary hemochromatosis, and complications connected to transplantation. Hence, the burden of SCD on health institutions is bound to increase steeply worldwide. At this stage, gene medicine remains unable to correct the HbS mutations in adults, and advances in the prevention of RBC hemolysis have stagnated since the discovery of hydroxy-urea.
The physiopathology of SCD involves an intricate combination of circulating and cardiovascular factors that have only been envisaged recently. The primary focus has been the biology of the erythrocyte for the past decades, aimed at blocking RBC remodeling to prevent anemia.
There are virtually no tests or indices predictive of VOC, or of vascular injury, or of the development of severe complications of the disease, besides clinical indicators that are generally identified properly only when the VOC has begun or when complications are already advanced. Futhermore, there are very few tool to identify properly the pstable patients that may best benefit from the current treatments such as blood transfusion programmes or hydoxyurea. Managing the side effects associated to these treatments remains challenging.
Amazingly, very little research efforts have been made regarding the toxic byproducts of hemolysis and their contribution to the disease. Poor understanding of the disease limits the development of novel therapeutic strategies.